Sensitivity to gluten, as measured by anti-gliadin antibodies, is about 5 or 6 times more common in persons with schizophrenia (about 20-30%) than in the general population (about 3-5%). Gluten Sensitivity (GS) is associated with a range of behavioral and neuropsychiatric disturbances. Most prior clinical trials of gluten-free diets reveal dramatic benefits for a subgroup of subjects with schizophrenia; small non-confirming trials are likely explained by sampling variation and the relative rarity of gluten sensitivity: tht is, the samples in some trials included few or no subjects who could be expected to benefit. A comprehensive interpretation for all the results is that ingestion of wheat in a subpopulation of GS individuals triggers an immune reaction which affects the central nervous system and produces the symptoms of schizophrenia. A prior application for a double-blind randomized controlled trial of a gluten-free diet for treatment of schizophrenia received a priority score of 5 and percentile rank of 18, not good enough for funding. This application for developmental work is responsive to the critiques of the reviewers who were concerned about the feasibility of the recruitment efforts, the ability to retain subjects in the inpatient phase of the trial, and the ablity of subjects to maintain the diet after the inpatient phase of the trial was completed. The plan is to sample from eight separate sources of potential subjects to evaluate which are most efficient in providing eligible and enthusiastic subjects, and to develop procedures which maximize success of recruitment into the 4-week-long inpatient trial. A pilot-size trial of gluten sensitive20 subjects will take place in a residential treatment unit at the Maryland Psychiatric Research Center, which will cover costs of inpatient treatment. Treatment and control groups will receive a gluten-free diet with addition of non-gluten starch in the treatment group and identical-appearing gluten in the control group. Subjects and assessors will be blind to the experimental condition. Procedures developed during this phase will help maximize retention in the future full trial. A two month maintenance phase after the inpatient period will develop procedures to maximize adherence to the gluten-free diet and to assess the benefits in this extended period. Assessments to be evaluated include BPRS scales for overall symptoms, SANS for negative symptoms, MATRICS for cognitive function, CSI and GSRS for gastrointestinal symptoms, and an array of immune parameters. Schizophrenia affects about 1.5 million people in the US, and about 20% of these-300,000-have gluten sensitivity. The basic hypothesis underlying treatment for schizophrenia has not changed for more than half a century, and new treatments are needed. This research addresses the NIH goal of advancing personalized medicine by developing targeted treatment for a subset of the schizophrenia population. Results would help elucidate etiologic pathways. An effective treatment that is inexpensive and without danger, such as a gluten-free diet, would have profound public health benefits.